Exploring the Chemical Diversity of Nucleic Acids

This seminar will describe our recent developments in two areas focused on modified nucleic acids. The first will detail our efforts to expand the chemical diversity of DNA aptamers to enable their evolution as antibody mimetics. To this end, our lab developed the Ligase-catalyzed OligOnucleotide PolymERization (LOOPER), which enables the high-fidelity sequence-defined incorporation of up to 256 modifications throughout a nucleic acid polymer in a library format. We demonstrated the utility of LOOPER by evolving a highly modified aptamer against human α-thrombin and evaluated the impact of modifications on affinity, selectivity, and structure. Recent developments on expanding the scope of LOOPER will be described. The second part will focus on our recent efforts in developing single-nucleotide resolution sequencing for RNA and DNA methylation. Using chemoselective reactions, we have developed chemistry-based next-generation sequencing methods that generate strong mutational signatures at methylation sites such as N6-methyladenosine and N2-methylguanosine. The approach and development of these methods as tools for epigenetic and epitranscriptomic research will be discussed.